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Title: Establishing the role of vitamin D signalling in immunity and melanoma specific survival
Author: Muralidhar, Sathya
ISNI:       0000 0004 7966 9427
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2019
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1α,25-dihydroxyvitamin D3 signals via its canonical nuclear receptor: Vitamin D Receptor (VDR). While higher levels of serum vitamin D have been reported to be associated with thinner primary melanomas and better outcome, increased VDR expression has been associated with decreased tumour progression and improved prognosis in melanoma primaries. However, the genomic basis of this effect remains to be explored and a causal mechanism is yet to be established. To address this question, I have used microarray data from a cohort of 703 treatment-naïve primary melanomas from the Leeds Melanoma Cohort (LMC) and corresponding clinical data. In the LMC primary melanomas, serum vitamin D was not significantly associated with melanoma survival. However, tumour VDR expression was significantly (and independently) protective for melanoma death in both the LMC and the TCGA metastatic melanoma datasets. Tumour VDR expression was found to be significantly positively correlated with genes enriched for ECM organization, TNF signalling, IFNg signalling, IL12-mediated signalling and NFkB signalling, which are predominantly immune-related. Concordantly, VDR expression was lower in tumours graded by the pathologist as having no immune infiltrate, compared to tumours with brisk and nonbrisk immune infiltrate. Additionally, VDR correlated positively with imputed immune cells scores. Conversely, the negatively correlated genes were enriched for Mitotic Prophase, Wnt signalling pathway, Mitochondrial translation, citric acid cycle and oxidative phosphorylation, which are predominantly proliferation-related. Of particular interest among the negatively correlated pathways was the Wnt/b-catenin signalling pathway. Functional validation using an in vivo tail-vein metastasis assay revealed that murine melanoma cells stably expressing VDR produced significantly fewer pulmonary metastases compared to control cells with null VDR expression. VDR-expressing cells also had significantly lower expression of Wnt/b-catenin signalling genes compared to control cells. These findings indicate that vitamin D-VDR signalling contributes to control of pro-proliferative and immunosuppressive Wnt/b-catenin signalling in melanoma and that this is associated with less proliferative, less metastatic disease and stronger host immune responses.
Supervisor: Newton-Bishop, Julia ; Bishop, David Timothy Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available